Imatinib compositions

ABSTRACT

The invention relates to a pharmaceutical composition, preferably a tablet, containing about 23-29% w/w imatinib and processes for its preparation.

CROSS REFERENCE TO RELATED APPLICATIONS

The present invention claims the benefit of the following U.S.Provisional Patent Application No. 60/995,321, filed Sep. 25, 2007; and60/995,651, filed Sep. 26, 2007. The contents of these applications areincorporated herein by reference.

FIELD OF THE INVENTION

The invention relates to formulations containing imatinib or apharmaceutical acceptable salt thereof, preferably imatinib mesylate inan amount of about 23-29% w/w of the total formulation.

BACKGROUND OF THE INVENTION

Imatinib mesylate,4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-[(4-pyrinin-3-yl)pyrimidin-2-yloamino]phenyl]benzamidemesylate, a compound having the chemical structure,

Imatinib is a protein-tyrosine kinase inhibitor, especially useful inthe treatment of various types of cancer and can also be used for thetreatment of atherosclerosis, thrombosis, restenosis, or fibrosis. Thusimatinib can also be used for the treatment of non-malignant diseases.Imatinib is usually administered orally in the form of a suitable salt,e.g., in the form of imatinib mesylate.

International Patent Application Nos. WO 99/03854, WO 2005/077933, WO2005/095379, WO 2004/106326, WO 2006/054314, WO 2006/024863, WO2006/048890, US 2006/0030568, WO 07/023,182 and U.S. Pat. No. 6,894,051apparently describe crystalline forms of imatinib mesylate designatedForms H1, α, α2, β, δ, ε, I, II, and amorphous. International PatentApplication No. WO 2007/136510 describes additional crystalline forms ofimatinib mesylate including forms V and X.

PCT application no. WO 03/090720 relates to formulations containingimatinib containing 30-80% w/w which were prepared using wetgranulation. These tablets are described as being of a small size andhence convenient to swallow despite the high dosage level of the activeingredient. However, these tablets express high friability and poorabrasion resistance, as well as limited flexibility in the amount ofexcipients usable due to the high drug load. In addition, the process tomanufacture such tablets is also difficult due to poor flow of the finalmixture and poor compressibility properties of such final mixture.Further, PCT application No. WO 01/47507 describes a pharmaceuticalcomposition/tablet containing about 22% w/w imatinib mesylate. Also, US2006/0275372 and WO 2007/119601 describe nanoparticulate compositions ofimatinib mesylate.

In view of the nature of this active ingredient, the high dosageadministered to patients and the problems reported regarding thedifficulties in tableting, it is an objective of the present inventionto further optimize tablets containing imatinib.

SUMMARY OF THE INVENTION

In one embodiment the present invention provides a pharmaceuticalcomposition, preferably a tablet containing imatinib or a pharmaceuticalacceptable salt thereof, preferably imatinib mesylate, in an amount ofabout 23-29% w/w of the total composition.

In another embodiment the present invention provides processes forpreparing a pharmaceutical composition, preferably a tablet, containingimatinib or a pharmaceutical acceptable salt thereof, preferablyimatinib mesylate, in an amount of about 23-29% w/w of the totalcomposition of by a process such as by dry granulation, or directcompression.

DETAILED DESCRIPTION

As used herein, the term “core” refers to an uncoated tablet.

As used herein, the term “% w/w” refers a weight of a substanceexpressed as a percentage of the total weight of the formulation. In thecase of a tablet containing imatinib mesylate: this is the weight ofimatinib mesylate expressed as a percentage of the total tablet weight,wherein the total weight is the weight of imatinib mesylate togetherwith excipients.

The present invention provides a pharmaceutical composition, preferablya tablet containing imatinib or a pharmaceutical acceptable saltthereof, preferably imatinib mesylate, in an amount of about 23-29% w/w,preferably of about 25-29% w/w, more preferably of about 28-29% w/w,that possess improved properties compared to prior art pharmaceuticalcompositions such as tablets with respect to hardness, friability,uniformity, homogeneous dispersibility, compressibility and flowability.Preferably, the tablet of the present invention has a hardness of atleast about 10 scu, more preferably at least about 15 scu, mostpreferably of about 15 scu to about 30 scu. The hardness of a tablet ismeasured by the force in kp (kilopond) or SCU (1 SCU=1.4 kp) required tobreak the tablet. Preferably, the tablet of the present invention has afriability of less than 1%, more preferably less than 0.5%, mostpreferably less than 0.1%. Friability can be defined as a measuredescribing whether a tablet can stay intact and withhold its form fromany outside force of pressure:

% friability=100×(W _(o) −W _(f))/W _(o)

where W_(o) is the original weight of the tablets, and W_(f) is thefinal weight of the tablets after the collection is put through thefriability tester.

Imatinib in the pharmaceutical composition, preferably tablet, of thepresent invention may be either in the form of a base or apharmaceutical acceptable salt, preferably, a mesylate salt. Mostpreferably, the imatinib mesylate is in a polymorphic form V or form X.Forms V and X are described in detail in co-pending U.S. applicationSer. No. 11/796,573, published as US 2008-0090833 (or as internationalpatent application WO 2007/136510), which is incorporated herein byreference.

Form V is characterized by data selected from the group consisting of: apowder XRD pattern with peaks at about 9.9, 11.7, 13.3, 16.6, and22.1±0.2 degrees two-theta; a powder XRD pattern with peaks at about9.9, 11.7, 13.3, and 16.6±0.2 degrees two-theta; a PXRD pattern havingpeaks at about: 5.6, 9.9, 11.7, 13.3, 16.6, and 18.5±0.2 degreestwo-theta; a PXRD pattern having at least five peaks selected from thelist consisting of peaks at about: 5.6, 9.9, 11.7, 13.3, 16.6, 18.5,22.1, 24.0, 26.2, 26.9±0.2 degrees two-theta; a solid-state ¹³C NMRspectrum with signals at about 162.8, 161.5, 158.5±0.2 ppm; asolid-state ¹³C NMR spectrum having chemical shifts differences betweenthe signal exhibiting the lowest chemical shift and another in thechemical shift range of 100 to 180 ppm of about 53.9, 52.6 and 49.6±0.1ppm.

Form X is characterized by data selected from the group consisting of: apowder XRD pattern with peaks at about 6.0, 8.6, 11.4, 14.2, 18.3±0.2degrees two-theta; a powder XRD pattern having peaks at about: 6.0, 8.6,10.2, 11.4, 14.2, 18.3±0.2 degrees two-theta; a powder XRD patternhaving at least five peaks selected from the list consisting of peaks atabout: 6.0, 8.6, 10.2, 11.4, 14.2, 17.8, 18.3, 21.6, 22.4, 23.6,24.8±0.2 degrees two-theta; a solid-state ¹³C NMR spectrum with signalsat about 159.9, 158.2 and 153.4±0.2 ppm; a solid-state ¹³C NMR spectrumhaving chemical shift differences between the signal exhibiting thelowest chemical shift and another in the chemical shift range of 100 to180 ppm of about 51.5, 49.8, and 45.0±0.1 ppm.

The pharmaceutical compositions, preferably tablets, of the inventioncontain imatinib or a pharmaceutical acceptable salt thereof, preferablyimatinib mesylate, in a mixture with one or more excipients. Excipientsare added to the composition for a variety of purposes as describedbelow. Preferably, the pharmaceutical composition of the presentinvention comprises a dosage form containing from about 50 mg to about500 mg imatinib, more preferably, from about 100 mg to about 400 mg,even more preferably about 100 mg or 400 mg imatinib.

The present invention also provides processes for preparing apharmaceutical composition, preferably a tablet, containing imatinib ora pharmaceutical acceptable salt thereof, preferably imatinib mesylatein an amount of about 23-29% w/w, preferably of 25-29% w/w, morepreferably of about 28-29% w/w.

One process of the invention for preparing such pharmaceuticalcomposition is dry granulation. The dry granulation may compriseblending the composition containing the active ingredient and theexcipients; compacting the blend into a slug or a sheet; comminuting theslug or the sheet into compacted granules; and compressing the compactedgranules into a tablet containing imatinib or a pharmaceuticalacceptable salt thereof, preferably imatinib mesylate in an amount ofabout 23-29% w/w.

Another process of the invention for preparing the pharmaceuticalcomposition is direct compression (dry blending). The direct compressionmay comprise blending the composition containing the active ingredientand the excipients; and compressing it directly into a tablet containingimatinib or a pharmaceutical acceptable salt thereof, preferablyimatinib mesylate in an amount of about 23-29% w/w. The compression isdirectly into a compacted dosage form using direct compressiontechniques. Direct compression is an easy, simple and applicable forindustrial scale.

Diluents increase the bulk of a solid pharmaceutical composition and canmake a pharmaceutical dosage form containing the composition easier forthe patient and caregiver to handle. Diluents for solid compositionsinclude, for example, microcrystalline cellulose (e.g. AVICEL®),microfine cellulose, lactose, starch, pregelatinized starch, calciumcarbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasiccalcium phosphate dihydrate, tribasic calcium phosphate, kaolin,magnesium carbonate, magnesium oxide, maltodextrin, mannitol,polymethacrylates (e.g. EUDRAGIT®), potassium chloride, powderedcellulose, sodium chloride, sorbitol and talc. Most preferably thediluents are selected from the group consisting of: Mannitol, calciumcarbonate, Starlac, lactose, and di-basic calcium phosphate, mostpreferably the diluent is Starlac (82-88% Lactose monohydrate and 12-18%Maize starch).

Solid pharmaceutical compositions that are compacted into a dosage formlike a tablet can include excipients whose functions include helping tobind the active ingredient and other excipients together aftercompression. Binders for solid pharmaceutical compositions include atleast one of acacia, alginic acid, carbomer (e.g. carbopol),carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guargum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropylcellulose (e.g. KLUCEL®), hydroxypropyl methyl cellulose (e.g.METHOCEL®), liquid glucose, magnesium aluminum silicate, maltodextrin,methylcellulose, polymethacrylates, povidone (e.g. KOLLIDON®,PLASDONE®), pregelatinized starch, sodium alginate, or starch. Morepreferably the binders are selected from hydroxypropylcellulose,povidone (e.g. KOLLIDON®, PLASDONE®), or starch, most preferably thebinder is povidone (e.g. KOLLIDON®, PLASDONE®).

The dissolution rate of a compacted solid pharmaceutical composition inthe patient's stomach can be increased by the addition of a disintegrantto the composition. Disintegrants include, but are not limited to,alginic acid, carboxymethylcellulose calcium, carboxymethylcellulosesodium (e.g. AC-DI-SOL @PRIMELLOSE®), colloidal silicon dioxide,croscarmellose sodium, crospovidone (e.g. KOLLIDON®, POLYPLASDONE®),guar gum, magnesium aluminum silicate, methyl cellulose,microcrystalline cellulose, polacrilin potassium, powdered cellulose,pregelatinized starch, sodium alginate, sodium starch glycolate (e.g.EXPLOTAB®) or starch. Most preferably the disintegrants are selectedfrom carboxymethylcellulose sodium (e.g. AC-DI-SOL @PRIMELLOSE®),crospovidone or sodium starch glycolate, most preferably thedisintegrant is crospovidone or carboxy methyl cellulose or mixturesthereof.

Glidants can be added to improve the flow properties of non-compactedsolid composition and improve the accuracy of dosing. Excipients thatcan function as glidants include colloidal silicon dioxide, magnesiumtrisilicate, powdered cellulose, starch, talc, and/or tribasic calciumphosphate. Most preferably the glidants are selected from talc,colloidal silicon dioxide, silicone dioxide NF most preferably theglidants is silicon dioxide NF.

When a dosage form such as a tablet is made by compaction of a powderedcomposition, the composition is subjected to pressure from a punch anddye. Some excipients and active ingredients have a tendency to adhere tothe surfaces of the punch and dye, which can cause the product to havepitting and other surface irregularities. A lubricant can be added tothe composition to reduce adhesion and ease release of the product formthe dye. Lubricants include, but are not limited to, magnesium stearate,calcium stearate, glyceryl monostearate, glyceryl palmitostearate,hydrogenated castor oil, hydrogenated vegetable oil, mineral oil,polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodiumstearyl fumarate, stearic acid, talc, and/or zinc stearate. Mostpreferably, the lubricants are selected from the group consisting of:sodium stearyl fumarate, magnesium stearate and talc. Most preferablythe lubricants are selected from the group consisting of magnesiumstearate, sodium stearyl fumarate and a mixture thereof.

Flavoring agents and flavor enhancers make the dosage form morepalatable to the patient. Common flavoring agents and flavor enhancersfor pharmaceutical products that can be included in the composition ofthe present invention include, but are not limited to, maltol, vanillin,ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, ortartaric acid.

Solid compositions can also be dyed using any pharmaceuticallyacceptable colorant to improve their appearance and/or facilitatepatient identification of the product and unit dosage level.

Selection of excipients and the amounts to use can be readily determinedby the formulation scientist based upon experience and consideration ofstandard procedures and reference works in the field.

In a preferred embodiment, the tablets in accordance with the presentinvention comprise; from about 23% to 29% w/w, more preferably fromabout 25% to about 29% w/w, imatinib mesylate; from 10 to 60% w/w, morepreferably from about 25% to about 60% w/w, of a diluent, filler orbulking agent, preferably lactose, more preferably starlac (82-88%Lactose monohydrate and 12-18% Maize starch); from 4 to 30% w/w, morepreferably from about 10% to about 25% w/w, of a disintegrant,preferably crospovidone; from 0.2 to 5% w/w of a glidant, preferablysilicon dioxide; and from 0.1 to 4% w/w, more preferably from about 0.5%to about 2% w/w, of a lubricant, preferably selected from magnesiumstearate or sodium stearyl fumurate or the mixture thereof.

More preferably, each tablet contains about;

119.5 mg imatinib mesylate

106.5 mg Starlac (82-88% Lactose monohydrate and 12-18% Maize starch)

52.0 mg crospovidone NF

22.50 mg Croscarmellose Sodium (Primellose),

2.0 mg Silicon Dioxide

102.5 mg A-Tab (Calcium Phosphate Dibasic)

3.5 mg magnesium stearate.

4.0 mg Sodium Stearyl Fumarate.

Having described the invention with reference to certain preferredembodiments, other embodiments will become apparent to one skilled inthe art from consideration of the specification. The invention isfurther defined by reference to the following examples describing indetail the preparation of the composition and methods of use of theinvention. It will be apparent to those skilled in the art that manymodifications, both to materials and methods, may be practiced withoutdeparting from the scope of the invention.

The following examples are given for the purpose of illustrating theinvention and shall not be construed as limiting the scope or spirit ofthe invention. The examples below demonstrate the advantage of thetablets having 23-29% Imatinib Mesylate, compared to tablets havingabout 60% of Imatinib Mesylate, in terms of hardness and friability.

EXAMPLES XRD Measurements

XRD diffraction was performed on X-Ray powder diffractometer:PanAlytical X'pert Pro powder diffractometer, Cu-tube, scanningparameters: CuKα radiation, λ=1.5418 Å. Continuous scan at a rate of:0.02° 2theta/0.3 sec.

13C NMR Measurements

The CP/MAS 13C NMR measurements were made at Bruker Avance 500 NMR US/WBspectrometer in 4-mm ZrO2 rotor. Magic angle spinning (MAS) speed was 10kHz. As used herein, the term “13C NMR chemical shifts” refers to theshifts measured under above specified conditions, however, these shiftscan slightly differ instrument to instrument and can be shifted eitherupfield or downfield due to the different instrumental setup andcalibration used. Nevertheless the sequence of individual peaks remainsidentical.

Example 1 Tablets Containing 23-29% Imatinib Mesylate (100 & 400 MgTablets) Prepared by Dry Granulation

MATERIAL 100, 400 mg % Part I Imatinib Mesylate 28.44 Silicone dioxide(Syloid 244 FP) 0.47 Starlac (Lactose Monohydrate 82-88% 25.22 MaizeStarch 12-18%) A-Tab (Calcium Phosphate Dibs Anh) 24.39Primilose(Croscarmellose Sodium) 2.67 Crospovidone 6.18 Part II SodiumStearyl Fumarate (PRUV) 0.95 Part III Crospovidone 6.18 Primelose(Croscarmelose Sodium) 2.67 Part IV Magnesium Stearate 0.83

Manufacturing process of Imatinib Mesylate tablets by dry granulation:

-   1. Sieve components of Part I through sieve #30 mesh and transfer to    Flow BIN.-   2. Sieve component of part II through #50 mesh, transfer to Flow Bin    from step 1 and mix for 20 minutes.-   3. Compress the mix from step 2 in to slugs.-   4. Mill the slugs from step 3 through Frewitt and transfer to Flow    Bin. And mix for 10 minutes.-   5. Sieve components of Part III through sieve #30 mesh and transfer    to Flow BIN from step 4 and mix for 15 minutes.-   6. Sieve component of part IV through sieve # 50 mesh, transfer to    Flow Bin from step 5 and mix for 3 minutes to get the final blend.-   7. Compress final blend from step 6 in to tablet cores (412 mg/tab    for 100 mg dosage strength and 1,648 mg/tab for 400 mg dosage    strength).

Cosmetic Coating:

1. Suspend 21S3894 ORANGE into 95% Ethanol under specified conditions.2. Apply suspension onto core tablets.

TABLE I Hardness and friability for the composition of example 1. Weight(mg) Hardness (scu) Friability (%) 1 414 21 0.0 2 411 18 3 409 19 4 41621 0.0 5 422 21 6 405 20 7 406 21 8 411 25 0.0 9 425 21 10 414 21 min405 18 max 425 25

Example 2 Tablets Containing 23-29% Imatinib Mesylate (100 & 400 MgTablets) Prepared by Direct Compression

MATERIAL mg/100 mg tablet Part I Imatinib Mesylate 119.5 Lactose MNHDR(DCL-14) 125.0 Crospovidone 62.0 Avicel PH 102 42.7 Klucel 12.8 Part IIAvicel PH 102 42.7 Aerosil 200 3.0 Part III Magnesium Stearate 4.3

Manufacturing process of Imatinib Mesylate tablets by dry granulation:

1. Mix components of Part I,2. Sieve components of Part II through sieve #30 mesh,3. Add materials of step 2 to the mixture of step 1 and mix for 10minutes,4. Sieve component of part III through #50 mesh,5. Add materials of step 4 to the mixture of step 3 and mix for 5minutes to get the final blend, and6. Compress the final blend from step 5 in to tablet cores (412 mg/tabfor 100 mg dosage strength and 1,648 mg/tab for 400 mg dosage strength).

TABLE II Hardness and friability for the composition of example 2 Weight(mg) Hardness (scu) Friability (%) 1 414 21 0.0 2 411 18 3 409 19 4 41621 0.0 5 422 21 6 405 20 7 406 21 8 411 25 0.0 9 425 21 10  414 21 min405 18 max 425 25

Example 3 Tablets Containing about 63% Imatinib Mesylate—Dry Granulation(Comparative Example) Imatinib Mesylate 100 mg Tablets:

mg per 1,000 Cores core Raw Materials kg g mg PART I (Slugging Mix)26.55 Starlac 26 55 2.8 Primellose 2 80 119.5 Imatinib Mesylate 119 5000.5 Silicon Dioxide NF(Syloid 500 244) 25.0 A-Tab (Calcium Phosphate 25000 Dibasic Anhydrous) 5.2 Kollidonh CL(Crospovidone 5 200 NF) Part II1.0 Sodium Stearyl Fumarate 1 000 (Pruv) 180.55 Theoretical End Weight180 550 for Slugging Mix Part III 3.0 Kollidon CL(Crospovidone) 3 0003.45 Primellose 3 450 Part IV 3.0 Magnesium Stearate NF/BP 3 000 190.0Theoretical End Weight 190 000

Example 4 Tablets Containing about 60% Imatinib Mesylate—DirectCompression (Comparative Example)

MATERIAL weight Part I Imatinib Mesylate 119.5 (Lactose Monohydrate)30.17 Crospovidone 18.5 Avicel PH 102 8.0 Klucel 3.0 Part II Avicel PH102 8.0 Aerosil 200 1.33 Magnesium Staearate 1.5

Example 5 Hardness and Friability of Tablets Containing about 60%Imatinib as Prepared in Examples 3 and 4

Weight (mg) Hardness (scu) Friability (%) 1 160 4 2.5 2 180 5 3 120 33.0 4 210 5 5 160 4 6 150 3 7 190 2 5.0 8 110 2 9 140 3 10 190 4

1. A pharmaceutical composition comprising imatinib mesylate in anamount of about 23-29% w/w of the total composition.
 2. Thepharmaceutical composition of claim 1, wherein the imatinib mesylate isa crystalline imatinib mesylate form V or crystalline imatinib mesylateform X.
 3. The pharmaceutical composition of claim 2, wherein imatinibmesylate is crystalline imatinib mesylate form X.
 4. The pharmaceuticalcomposition of claim 1, comprising imatinib mesylate in an amount ofabout 25-29% w/w of the total composition.
 5. The pharmaceuticalcomposition of claim 4, comprising imatinib mesylate in an amount ofabout 28-29% w/w of the total composition.
 6. The pharmaceuticalcomposition of claim 1 in the form of a tablet.
 7. The pharmaceuticalcomposition of claim 6, wherein the hardness of the tablet is at leastabout 10 scu.
 8. The pharmaceutical composition of claim 7, wherein thehardness of the tablet is at least about 15 scu.
 9. The pharmaceuticalcomposition of claim 8, wherein the hardness of the tablet is about 15scu to about 30 scu.
 10. The pharmaceutical composition of claim 6,wherein the tablet has a friability of less than 1%.
 11. Thepharmaceutical composition of claim 10, wherein the tablet has afriability of less than 0.1%.
 12. The pharmaceutical composition ofclaim 6, wherein the tablet comprises a dosage of about 50 mg to about500 mg imatinib.
 13. The pharmaceutical composition of claim 12,comprising a dosage selected from a 100 mg dosage and a 400 mg dosage ofimatinib.
 14. The pharmaceutical composition of claim 1, comprisingimatinib mesylate in an amount from about 23 to about 29% w/w; fromabout 10 to about 60% w/w of a diluent; from about 4 to about 30% w/w ofa disintegrant; from about 0.2 to about 5% w/w of a glidant; and fromabout 0.1 to about 4% w/w of a lubricant.
 15. The pharmaceuticalcomposition of claim 14, wherein the diluent is a lactose monohydrate(Starlac), the disintegrant is selected from crospovidone,carboxymethylcellulose sodium and a mixture thereof, the glidant issilicon dioxide, and the lubricant is magnesium stearate, sodium stearylfumarate or a mixture thereof.
 16. The pharmaceutical composition ofclaim 14, comprising imatinib mesylate in an amount from about 23 toabout 29% w/w; from about 25 to about 60% w/w of the diluent; from about10 to about 25% w/w of the disintegrant; from about 0.2 to about 5% w/wof the glidant; and from about 0.5 to about 2% w/w of the lubricant. 17.The pharmaceutical composition of claim 6, comprising about 119.5 mgimatinib mesylate; about 106.5 mg of a lactose monohydrate (Starlac);about 52 mg crospovidone; about 22.5 mg croscarmellose sodium(Primellose); about 2 mg silicon dioxide; about 102.5 mg calciumphosphate dibasic (A-Tab); about 3.5 mg magnesium stearate; and about 4mg sodium stearyl fumarate.
 18. A process of preparing a pharmaceuticalcomposition of claim 1 containing imatinib mesylate in an amount ofabout 23-29% w/w of the total composition comprising: combining imatiniband at least one pharmaceutical acceptable excipient to form mixture andtabletting the mixture into a pharmaceutical composition in the form ofa tablet.
 19. The process of claim 18, wherein the imatinib mesylate iscrystalline imatinib mesylate form V or form X.
 20. The process of claim18, wherein tabletting comprises a method selected from dry granulation,and direct compaction of a mixture comprising imatinib.
 21. The processof claim 20, wherein tabletting comprises dry granulation.
 22. Theprocess of claim 20, wherein tabletting comprises direct compression.23. The process of claim 18, further comprising coating thepharmaceutical composition in the form of a tablet with a cosmeticcoating.